Interferon gene therapy reprograms the leukemia microenvironment inducing protective immunity to multiple tumor antigens

G Escobar, L Barbarossa, G Barbiera, M Norelli, M Genua, A Ranghetti, T Plati, B Camisa, C Brombin, D Cittaro, A Annoni, A Bondanza, R Ostuni, B Gentner, L Naldini

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Abstract

Immunotherapy is emerging as a new pillar of cancer treatment with potential to cure. However, many patients still fail to respond to these therapies. Among the underlying factors, an immunosuppressive tumor microenvironment (TME) plays a major role. Here we show that monocyte-mediated gene delivery of IFNα inhibits leukemia in a mouse model. IFN gene therapy counteracts leukemia-induced expansion of immunosuppressive myeloid cells and imposes an immunostimulatory program to the TME, as shown by bulk and single-cell transcriptome analyses. This reprogramming promotes T-cell priming and effector function against multiple surrogate tumor-specific antigens, inhibiting leukemia growth in our experimental model. Durable responses are observed in a fraction of mice and are further increased combining gene therapy with checkpoint blockers. Furthermore, IFN gene therapy strongly enhances anti-tumor activity of adoptively transferred T cells engineered with tumor-specific TCR or CAR, overcoming suppressive signals in the leukemia TME. These findings warrant further investigations on the potential development of our gene therapy strategy towards clinical testing. © 2018, The Author(s).
Original languageEnglish
Article number2896
JournalNature Communications
Volume9
DOIs
Publication statusPublished - 2018

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interferon
gene therapy
Gene therapy
leukemias
immunity
Neoplasm Antigens
antigens
Genetic Therapy
Interferons
Tumor Microenvironment
Tumors
Immunity
Leukemia
tumors
Immunosuppressive Agents
T-cells
Single-Cell Analysis
T-Lymphocytes
Neoplasms
mice

Cite this

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title = "Interferon gene therapy reprograms the leukemia microenvironment inducing protective immunity to multiple tumor antigens",
abstract = "Immunotherapy is emerging as a new pillar of cancer treatment with potential to cure. However, many patients still fail to respond to these therapies. Among the underlying factors, an immunosuppressive tumor microenvironment (TME) plays a major role. Here we show that monocyte-mediated gene delivery of IFNα inhibits leukemia in a mouse model. IFN gene therapy counteracts leukemia-induced expansion of immunosuppressive myeloid cells and imposes an immunostimulatory program to the TME, as shown by bulk and single-cell transcriptome analyses. This reprogramming promotes T-cell priming and effector function against multiple surrogate tumor-specific antigens, inhibiting leukemia growth in our experimental model. Durable responses are observed in a fraction of mice and are further increased combining gene therapy with checkpoint blockers. Furthermore, IFN gene therapy strongly enhances anti-tumor activity of adoptively transferred T cells engineered with tumor-specific TCR or CAR, overcoming suppressive signals in the leukemia TME. These findings warrant further investigations on the potential development of our gene therapy strategy towards clinical testing. {\circledC} 2018, The Author(s).",
author = "G Escobar and L Barbarossa and G Barbiera and M Norelli and M Genua and A Ranghetti and T Plati and B Camisa and C Brombin and D Cittaro and A Annoni and A Bondanza and R Ostuni and B Gentner and L Naldini",
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TY - JOUR

T1 - Interferon gene therapy reprograms the leukemia microenvironment inducing protective immunity to multiple tumor antigens

AU - Escobar, G

AU - Barbarossa, L

AU - Barbiera, G

AU - Norelli, M

AU - Genua, M

AU - Ranghetti, A

AU - Plati, T

AU - Camisa, B

AU - Brombin, C

AU - Cittaro, D

AU - Annoni, A

AU - Bondanza, A

AU - Ostuni, R

AU - Gentner, B

AU - Naldini, L

PY - 2018

Y1 - 2018

N2 - Immunotherapy is emerging as a new pillar of cancer treatment with potential to cure. However, many patients still fail to respond to these therapies. Among the underlying factors, an immunosuppressive tumor microenvironment (TME) plays a major role. Here we show that monocyte-mediated gene delivery of IFNα inhibits leukemia in a mouse model. IFN gene therapy counteracts leukemia-induced expansion of immunosuppressive myeloid cells and imposes an immunostimulatory program to the TME, as shown by bulk and single-cell transcriptome analyses. This reprogramming promotes T-cell priming and effector function against multiple surrogate tumor-specific antigens, inhibiting leukemia growth in our experimental model. Durable responses are observed in a fraction of mice and are further increased combining gene therapy with checkpoint blockers. Furthermore, IFN gene therapy strongly enhances anti-tumor activity of adoptively transferred T cells engineered with tumor-specific TCR or CAR, overcoming suppressive signals in the leukemia TME. These findings warrant further investigations on the potential development of our gene therapy strategy towards clinical testing. © 2018, The Author(s).

AB - Immunotherapy is emerging as a new pillar of cancer treatment with potential to cure. However, many patients still fail to respond to these therapies. Among the underlying factors, an immunosuppressive tumor microenvironment (TME) plays a major role. Here we show that monocyte-mediated gene delivery of IFNα inhibits leukemia in a mouse model. IFN gene therapy counteracts leukemia-induced expansion of immunosuppressive myeloid cells and imposes an immunostimulatory program to the TME, as shown by bulk and single-cell transcriptome analyses. This reprogramming promotes T-cell priming and effector function against multiple surrogate tumor-specific antigens, inhibiting leukemia growth in our experimental model. Durable responses are observed in a fraction of mice and are further increased combining gene therapy with checkpoint blockers. Furthermore, IFN gene therapy strongly enhances anti-tumor activity of adoptively transferred T cells engineered with tumor-specific TCR or CAR, overcoming suppressive signals in the leukemia TME. These findings warrant further investigations on the potential development of our gene therapy strategy towards clinical testing. © 2018, The Author(s).

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